Bladder cancer is the most common urologic malignancy and is responsible for an appreciable number of deaths each year in the USA. Aside from tobacco smoking and certain occupational exposures, the etiology of this malignancy remains largely unexplained. Accumulating evidence indicates that bladder cancer comprises a heterogeneous group of tumors with distinct molecular-pathologic characteristics. Moreover, the pattern of somatic changes (including promoter methylation silencing of tumor suppressor genes and TP53 alterations) may reflect exposures to specific carcinogens and serve as markers of aggressive, i.e., fatal, disease. Therefore, we propose to investigate the etiologic role of exposure to known and suspected bladder carcinogens on (1) promoter methylation silencing of the tumor suppressor genes currently known to contribute to the genesis of bladder cancer and (2) global hypomethylation (i.e., hypomethylation of LINE elements). Further, we will determine the impact of methylation alterations on clinical phenotype (e.g., tumor stage and grade) and bladder cancer patient survival. Lastly, applying novel statistical methods, we will build a model of somatic epigenetic and TP53 alterations to examine whether exposure history (e.g., cigarette smoking, occupation, diet, arsenic exposure, and hair dye use) and variation in DNA repair and carcinogen metabolism genes modify the associations with molecular-pathologic phenotype and clinical outcome in bladder cancer. Our study takes advantage of population-based investigations of bladder cancer in New Hampshire encompassing approximately 850 bladder cancer patients on whom detailed exposure, medical and family history, blood or buccal DNA, and diagnostic tumor tissue samples are being successfully ascertained. In addition, we are utilizing novel statistical approaches to determine the etiologic and clinical importance of silencing genes involved in bladder cancers. The results of our study will help clarify the role of environmental and genetic factors in the pathogenesis of bladder cancer, the underlying mechanisms of bladder cancer induction by these factors, and the utility of molecular markers in predicting bladder cancer prognosis. This work, then, will use a novel approach to evaluate the importance of silencing genes that cause bladder cancer. It will develop approaches that will enlarge our understanding of how exposures induce bladder cancer, demonstrate the utility of molecular markers in predicting prognosis and clarify the causal role of many exposures in bladder cancer.